The objective of this research is to identify central neurochemical changes that occur during stress and to determine if these changes aid in the development of adaptation and resistance to stress. In previous work on this project we have found that chronic stress in rats leads to a reduction in the sensitivity of brain norepinephrine (NE) receptors. Since there is evidence that subsensitivity to NE is one of the factors leading to resistance to stress and is also an important factor in antidepressant therapy, the present research will be directed toward a further study of this phenomenon. The first aim of the proposed research is to obtain basic information on the mechanism of stress-induced subsensitivity which will facilitate subsequent investigation of its function. This will be accomplished (a) by determining the minimum amount of stress necessary to induce subsensitivity, (b) by studying the physiological and endocrinological events that lead to this change, and (c) by defining the molecular basis of this phenomenon. Data obtained from these studies will be used to develop methods to experimentally manipulate subsensitivity in order to test its role in adaptation. The second aim of the project is to determine if stress-induced subsensitivity is an adaptive response which aids in the development of resistance to stress. This will be studied (a) by determining if subsensitivity to NE occurs during the development of resistance to various forms of stress, and (b) by determining if animals who are made subsensitive to NE prior to stress by pretreatment with antidepressant drugs, stress hormones or adrenergic blocking agents show an increased resistance to subsequent stress. In addition to providing basic information on stress adaptation the present research will also provide data on the related hypothesis that adaptation to stress and antidepressant therapy are analagous phenomena both mediated by the same set of central neurochemical changes. The latter hypothesis will stimulate research on the development of new therapeutic approaches to depression involving stress hormones and adaptation to mild stressors such as exercise.